This research was designed to clarify the roles of obesity and physical inactivity in the pathogenesis of the deterioration in insulin sensitivity and reductions in HDL-C and glucose tolerance which occur in obese older men. Oral glucose tolerance tests (OGTT) and hyperinsulinemic euglycemic clamps at 100 mU/m2.min insulin infusion rates were performed and lipoprotein lipids measured in 36 healthy older 45-75 yr old and 13 younger (19-36 yr) men with wide ranges of obesity (% body fat: 5-39%), body fat distribution (WHR: 0.79-1.07) and maximal aerobic capacity (VO2max: 15-58 ml/kgmin). To control for obesity and steady state plasma insulin levels during clamps (I), glucose metabolized (M) was normalized for both fat free mass (FFM) and I (mg/kg FFMmin(uU/ml)-] and designated M/I. Insulin sensitivity declined with age, and correlated negatively with % body fat and WHR and positively with V02max; in multiple regression analyses, the only significant independent predictor of insulin sensitivity was V02max. in older and younger men matched for VO2max, WHR, or % body fat, there were no significant differences in M/I. In contrast, M/I was significantly lower in the older men with either a lower V02;max, higher WHR, or greater % body fat. Plasma HDL-C levels correlated negatively with % body fat and directly with insulin sensitivity; in multiple regression analyses insulin sensitivity and % body fat were the only independent predictors of HDL-C levels. Weight loss (WL) and exercise training (ET) reversed the decline in insulin sensitivity and low HDL-C levels in obese older men; WL in 6 and ET in 4 men improved M/I and HDL-C levels. Thus, the declines in insulin sensitivity, glucose tolerance and HDL-C which occur in obese older men seem modifiable by interventions which increase physical fitness and reduce body weight. This research is collaborative effort of scientists in the Metabolism Section, LCP , NIA and the Division of Geriatric Medicine, Department of Medicine, Johns Hopkins University at Francis Scott Key Medical Center.